1. Field of the Invention
The cephalosporins of the present invention in general possess the usual attributes of such compounds and are particularly useful in the treatment of bacterial infections.
2. Description of the Prior Art
The cephalosporins are a well-known group of semisynthetic antibacterial agents made originally, for example, by acylation of the 7-amino group of the nucleus 7-aminocephalosporanic acid (7-ACA) and later by similar acylation of nuclei derived therefrom, as by modification of its substituent at the 3-position. Various reviews have appeared in the scientific literature (e.g. Cephalosporins and Penicillins - Chemistry and Biology, edited by Edwin H. Flynn, Academic Press, New York, 1972, and particularly pages 554-569) and in the patent literature, e.g. as in U.S. Pat. Nos. 3,687,948; 3,741,965; 3,743,644; 3,759,904; 3,759,905; 3,766,175; 3,766,906; 3,769,281; 3,796,801; 3,799,923; 3,812,116; 3,813,388; 3,814,754 and 3,814,755 (all U.S. Class 260-243C).
Issued patents on 3-thiolated cephalosporins in which the 7-substituent is
(a) .alpha.-Amino-.alpha.-phenylacetamido include U.S. Pat. Nos. 3,641,021; 3,734,907; 3,687,948; 3,741,965; 3,757,015; 3,743,644, Japan No. 71/24400 (Farmdoc 46374S), Belgium No. 776,222 (Farmdoc 38983T; U.K. No. 1,328,340 which includes various substituents on the benzene ring), Belgium No. 772,592 (Farmdoc 19696T; U.S. Pat. Nos. 3,687,948, 3,734,907 and 3,757,012), West Germany No. 2,202,274 (Farmdoc 50428T) corresponding to U.S. Pat. No. 3,759,904, Netherlands No. 7205644 (Farmdoc 76309T; U.S. Pat. No. 3,757,014); and
(b) o-, m- or p-aminoethoxyphenylacetamido as Netherlands No. 72/13968 (Farmdoc 2474OU) corresponding to U.S. Pat. No. 3,759,905 and
(c) o-aminomethylphenylacetamido as U.S. Pat. Nos. 3,766,176 and 3,766,175 (which also review the older patent literature concerning substituted 7-phenylacetamidocephalosporanic acids) and
(d) N-(phenylacetimidoyl)aminoacetamido as U.S. Pat. No. 3,692,779; and
(e) .alpha.-amino-.alpha.-(1,4-cyclohexadienyl)acetamido as in Belgium No. 776,222 (Farmdoc 38983T; U.K. No. 1,328,340).
Additional similar disclosures are found in U.S. Pat. No. 3,692,779 (Belgium No. 771,189; Farmdoc 12819T), Japan No. 72/05550 (Farmdoc 12921T), Japan No. 72/05551 (Farmdoc 12922T), U.S. Pat. No. 3,719,673 (Belgium No. 759,570; Farmdoc 39819S), Belgium No. 793,311 (Farmdoc 39702U) and Belgium No. 793,191 (Farmdoc 39684U).
Issued disclosures of 3-thiolated cephalosporins in which the 7-substituent is 7-mandelamido (7-.alpha.-hydroxyphenylacetamido) are found, for example, in U.S. Pat. No. 3,641,021, France No. 73.10112, U.S. Pat. No. 3,796,801, Great Britain No. 1,328,340 (Farmdoc 38983T), U.S. Pat. No. 3,701,775, Japan No. 48-44293 (Farmdoc 55334U) and in Hoover et al., J. Med. Chem. 17(1), 34-41 (1974) and Wick et al., Antimicrobial Ag. Chemo., 1(3), 221-234 (1972).
U.S. Pat. No. 3,819,623 (and, for example, also U.K. No. 1,295,841 and West Germany No. 1,953,861) discloses specifically and with working details the preparation of 2-mercapto-1,3,4-thiadiazole-5-acetic acid and its conversion to 7-(1H-tetrazol-1-yl-acetamido)-3-(5-carboxymethyl-1,3,4-thiadiazol-2-ylthi omethyl)-3-cephem-4-carboxylic acid which is also disclosed in West Germany Offenlegungsschrift No. 2,262,262.
U.S. Pat. Nos. 3,766,175 and 3,898,217 disclose a compound of the formula ##STR1## wherein R is ##STR2## or a nontoxic, pharmaceutically acceptable salt thereof, and
A compound of the formula ##STR3## wherein
R is --H or lower alkyl;
R.sup.1 is --H, (lower)alkanoyloxy, ##STR4## n is an integer from 4-7, inclusive; and the pharmaceutically acceptable addition salts thereof, respectively.
U.S. Pat. Nos. 3,883,520 and 3,931,160 and Farmdoc Abstract 22850W make reference to 3-heterocyclicthiomethyl cephalosporins containing a number of substituents (including carboxyl) on the numerous heterocycles included but these references are completely general in nature and include no physical constants, yields, methods of synthesis or the like and do not even name any such compound containing a carboxyl substituent.
U.S. Pat. No. 3,928,336 provides a review of much of the older cephalosporin art.
U.S. Pat. Nos. 3,907,786 and 3,946,000 disclose cephalosporins containing various fused ring bicyclic thiols.
Farmdoc abstract 18330X discloses compounds of the formula ##STR5## (where R.sup.1 =acyl or H; R.sup.3 =H or methoxy; n=1-9).